Tricyclic compounds useful as inhibitors of farnesyl protein transferase (FPT) are known in the art.
WO97/23478 published Jul. 3, 1997 discloses the preparation of an intermediate useful in the preparation of FPT inhibitors. The intermediate 
is prepared by reacting 
with diisobutylaluminum hydride followed by separation of the racemic mixture using a chiralpak AD column.
Processes which provide improved yields of the above intermediate would be a welcome contribution to the art. This invention provides such a process.
This invention provides a process for producing a compound of the formula: 
comprising:
(1) separating the atropisomers of 
xe2x80x83to obtain the atropisomers 
(2) heating the atropisomer of formula 2.0B at a suitable temperature in a suitable solvent to obtain a mixture of atropisomers of formulas 2.0A and 2.0B;
(3) separating the atropisomers of formulas 2.0A and 2.0B of step (2); and
(4) reducing the atropisomer of formula 2.0A to obtain a compound of formula 1.0;
wherein:
R1, R2, and R3 are independently selected from halogen (i.e., Cl, Br, or I), C1 to C6 alkyl or xe2x80x94OR4 wherein R4 is a C1 to C6 alkyl.
Preferably, R1 is Br, R2 is Cl and R3 is Brxe2x80x94i.e., preferably this invention provides a process for producing a compound of the formula: 
comprising:
(1) separating the atropisomers of 
xe2x80x83to obtain the atropisomers 
(2) heating the atropisomer of formula 2.1B at a suitable temperature in a suitable solvent to obtain a mixture of atropisomers of formulas 2.1A and 2.B;
(3) separating the atropisomers of formulas 2.1A and 2.1B of step (2); and
(4) reducing the atropisomer of formula 2.1A to obtain a compound of formula 1.1.
The process of this invention provides the compound of formula 1.0 (preferably 1.1) as the specific (R)-isomerxe2x80x94i.e., no racemic mixture (based on C-11) is produced in the reduction step. Those skilled in the art will appreciate that C-11 position in the tricyclic ring is 
The intermediate compound of formula 1.1 is useful in the preparation of FPT inhibitors disclosed, for example, in WO97/23478. Thus, the compound of formula 1.1 is useful in the preparation of: 
In the process of this invention atropisomer 2.0A obtained in step 1 above can be reduced while additional atropisomer 2.0A is being obtained in steps 2 and 3 above. Thus, atropisomer 2.0A from step 1 above can be reduced as soon as it is obtained. Alternatively, atropisomer 2.0A obtained from step 1 above can be combined with atropisomer 2.0A obtained from steps 2 and 3 above, and the total amount of atropisomer 2.0A can be reduced at one time. Steps 2 and 3 above can be repeated to obtain additional atropisomer 2.0A from atropisomer 2.0B.
Preferably, formula 2.0 is separated, in step 1, into its atropisomers using HPLC and a suitable column (i.e., a column that will provide the desired degree of separation in a reasonable amount of time). Preferably, for separating compound 2.1, the column is packed with amylose tris(3,5-dimethylphenyl carbamate) coated on a 10 micron silica gel. This column is commercially available under the tradename Chiralpak AD.
A suitable elution solvent is used to obtain separation of the atropisomers. A suitable solvent is one which provides the desired degree of polarity to sufficiently separate the isomers in a reasonable amount of time. For example, the solvent can comprise: (1) a low boiling alcohol (e.g., isopropanol, methanol, ethanol, mixtures thereof, or the like); (2) a low boiling organic co-solvent (e.g., hexane, pentane, heptane, mixtures thereof, or the like); and (3) an organic base (e.g., diethylamine, diisopropylamine, triethylamine, mixtures thereof, or the like). The solvent, for example, can comprise from about 15 to about 35% alcohol, and about 40 to about 85% organic co-solvent, and about 0.1 to about 1% base, such that the total amount equals 100%v/v. For example, the elution solvent can comprise about 15 to about 35% isopropyl alcohol, and about 40 to about 85% hexane, and about 0.1 to about 1% diethylamine such that the total amount equals 100%v/v. Preferably, for compound 2.1, the elution solvent comprises 35% isopropyl alcohol and 0.2% diethylamine in hexane.
To convert atropisomer 2.0B to a mixture of atropisomers 2.0A and 2.0B, atropisomer 2.0B is heated at a suitable temperature in a suitable organic solvent. For example, atropisomer 2.0B can be heated to 100 to 200xc2x0 C. in an appropriate high boiling solvent. Generally, atropisomer 2.0B is heated to reflux in the solvent. Examples of solvents include dimethyl formamide, toluene, and and 1,2-dichlorobenzene. Preferably, atropisomer 2.1B is heated in 1,2-dichlorobenzene at a temperature of about 150xc2x0 C.
The atropisomer of formula 2.0A is reduced using a suitable reducing agent. Preferably, diisobutylaluminum hydride is used. The reduction is carried out using conditions well known to those skilled in the art. For example, atropisomer 2.0A can be dissolved in a suitable organic solvent (e.g., toluene) to which a suitable amount of diisobutylaluminum hydride is added to effectively reduce 2.0A. The solution is then refluxed under nitrogen. The desired product can then be isolated by known separation procedures.